Download Background: Classical fear conditioning is a phenomenon in which

Background: Classical fear conditioning is a phenomenon in which a neutral conditioned
stimulus (CS) is paired with a naturally aversive unconditioned stimulus (US) leading the
CS to evoke a fearful reaction even in absence of the US (Pavlov, 1927). In some cases, this
fear of the conditioned danger cue (CS+) can also be observed when a subject is presented a
stimulus that shares similar characteristics with the CS+. This is known as fear generalization.
Although some amount of generalization is normal, over generalizing to the CS+ has been
implicated as a marker of several anxiety disorders, including panic disorder and PTSD (Lissek
et al., 2010). Using single cell recordings of neurons in primary sensory cortex of animals,
conditioning dependent plasticity studies track changes in the sensory representation of the
CS+ from pre- to post-conditioning. Results at post-versus pre-conditioning demonstrate that
the neural representations of stimuli shift when that stimuli has been paired with a US . The
neural representations of the CS+ expand and begin to overlap with perceptually similar stimuli
that have never been paired with the aversive US. As such, by way of conditioning, the same
neurons come to be activated by both the CS+ and the resembling stimuli (Weinberger , 2007)
. This overlap in neural representation increases the likelihood that presentation of a resembling
generalization stimulus will activate the representation of the CS+ , resulting in a heightened fear
response.
Hypothesis: Retinotopic mapping will reveal conditioning dependent plasticity in sensory
representations of the conditioned danger cue that corresponds with levels of observed fear
generalization.
Research Plan and Methods: Because single cell recording is not possible in human subjects,
I will use fMRI and retinotopic mapping as a way of studying conditioning dependent neuronal
plasticity that may subserve generalization. Scott Murray’s lab at the University of Washington
has designed a series annuli, or rings, of increasing size (Murray, 2006). Because neurons in the
human primary visual cortex (i.e., calcarine sulcus) are organized according to the eccentricity,
or location in relation to the center-of gaze, each ring size has a distinct neural representation,
with the smallest ring represented most posterior on the calcarine and increasing ring sizes
represented on increasingly anterior portions of this sulcus. These rings will be designed
and presented in a way to maximize primary visual cortex activation. The stimulus rings are
presented below. For half of the participants, the largest ring will be paired with electric shock
and serve as the CS+ and the smallest will serve as a conditioned safety cue (CS-). For the other
half, this will be reversed.
The experiment will have three parts:
1)
Preacquisition: During preacquisition, each of the stimuli will be presented without any
shock in order to establish the preconditioning hemodynamic response in the calcarine sulcus
and maps of neuronal representation.
2)
Acquisition: Acquisition will consist of presenting the CS+ accompanied by an electric
shock US and the CS- accompanied by no shock, as well as a V shaped control stimulus,
designed to ensure that the subject is not generalizing fear to all things circular .
3)
Generalization: During generalization, all sizes of rings and the V will be presented. In
addition to the functional images, we will also collect online subjective ratings of perceived level
of risk for shock, as well as skin conductance as a measure of physiological arousal, in order to
determine how well the subject has learned the connection between the shock US and the CS+ .
Anticipated Results: I expect to be able to map the retinotopic representations of the different
ring sizes before and after acquisition and use this map to determine if conditioning causes
a change in representation. I also anticipate being able to determine if there is a correlation
between the amount of generalization evident from behavioral assays and the amount of
representational shift in the brain.
Intellectual Merit and Broader Impact: My advisor, Shmuel Lissek, has pioneered the
experimental study of conditioned fear generalization in anxiety disorders. Steven Engle, who
developed the retinotopic mapping technique applied herein, is an active collaborator on this
project and will provide expertise on human retintopy with fMRI. This research will take place
at the University of Minnesota’s Center for Magnetic Resonance Research, a bio-imaging center
with multiple research dedicated MRI machines. Dr. Lissek has pre-paid time on the Center’s 3T
magnet reserved for completion of this project. I have taken courses in fMRI research and have
been working with Phil Burton, an expert in fMRI preprocessing and analysis, to learn methods
for data analysis.
Animal data on conditioning-dependent plasticity in sensory representations of the CS+
suggest that the emotional meaning of sensory stimuli can be encoded in primary sensory cortex .
The current project will test the degree to which primary sensory cortex codes for emotional
meaning in humans, which addresses a fundamental question regarding the purview of primary
sensory cortex. Additionally, because conditioning-induced plasticity in animals produces an
overlap in the neural representation of the CS+ and resembling stimuli, this plasticity is a
promising neural substrate of conditioned-fear generalization, a ubiquitous associative learning
process that allows a person to transfer knowledge from previous experiences to future
resembling encounters. The results from this study will be submitted to a peer-reviewed
publication and will ideally serve as the pilot for another grant.